Growth factors are substances, such as polypeptide hormones, which affect the growth of defined populations of animal cells in vivo or in vitro, but which are not nutrient substances. Proteins involved in the growth and differentiation of tissues may promote or inhibit growth, and promote or inhibit differentiation, and thus the general term "growth factor" includes cytokines and trophic factors. Among growth, or neurotrophic, factors presently known are the transforming growth factors (TGF-.alpha., TGF-.beta., TGF-.gamma.)]. Transforming growth factor-.beta. appears to elicit a variety of responses in many different cell types.
Receptors that affect growth (that is, receptors for growth-associated ligands) are proteins found associated with cell surfaces that specifically bind their growth factors as ligands. Growth factor receptors are utilized in various clinical and diagnostic applications, such as are described by: U.S. Pat. No. 4,857,637, issued Aug. 15, 1989, inventors Hammonds et al. (a method for immunizing an animal against its growth hormone receptor through use of vaccinating with antibodies); U.S. Pat. No. 4,933,294, issued Jun. 12, 1990, inventors Waterfield et al. (studies of structural alterations of the human EGF receptor and its gene and a relationship in tumorigenesis for assays and therapies involving the human EGF receptor); and U.S. Pat. No. 5,030,576, issued Jul. 9, 1991, inventors Dull et al. (use of receptor growth factors, in designing drugs by the pharmaceutical industry, and use of a receptor hybrid for screening drug purposes). DNA encoding several different receptors for TGF-.beta. has recently been described by Lin et al., PCT application WO93/09228, published May 13, 1993. The availability of the TGF-.beta. receptors will facilitate further assessments of TGF-.beta. functions.
Kanzaki et al., U.S. Pat. No. 5,177,197, issued Jan. 5, 1993, describe a DNA which expresses a protein known as platelet TGF-.beta. 1-BP. The protein is said to be useful for producing anti-sera in order to identify complexes containing the binding protein, as well as in formation of labeled probes.
Widespread neuronal cell death accompanies normal development of the central and peripheral nervous systems. Studies of peripheral target tissues during development have shown that neuronal cell death results from the competition among neurons for limiting amounts of survivor factors ("neurotrophic factors"). The earliest identified of these, nerve growth factor ("NGF"), is the most fully characterized and has been shown to be essential for the survival of sympathetic and neural crest-derived sensory neurons during early development of both chick and rat. Barde et al., U.S. Pat. No. 5,229,500, issued Jul. 20, 1993, describe nucleic acid sequences encoding brain derived neurotrophic factor ("BDNF"), as well as the BDNF protein. BDNF is suggested for treating Parkinson's Disease and Alzheimer's Disease. Additional uses (quite recently performed successfully) are for the identification of homologous regions between BDNF and NGF so as to identify and isolate additional members of the NGF family, and also to generate immunogen by antibodies directed toward BDNF or fragments.
Among the exciting new possibilities for neurotrophic factors are applications involving neural tissue, such as to prevent degradation of dopaminergic neurons in treating Parkinson's disease. One of the most recently isolated new proteins appears selectively to promote survival of the neurons that secrete the neurotransmitter dopamine. Lin et al., Science, 260, pp. 1130-1132 (1993). This new neurotropic factor is a glial derived neurotrophic factor and is said to be distantly related to the TGF-.beta. superfamily.
Many members of the TGF-.beta. super family have been characterized. For example, Basler et al. have graphically represented the sequence relationship between members of the TGF-.beta. superfamily. Cell, 73, pp. 687-702 (1993).
Also among TGF-.beta. members are the bone morphogenetic proteins (BMP). The BMPs have been indicated as useful in wound healing, tissue repair, and to induce cartilage and/or bone growth. For example, PCT Application 9309229, inventors Israel and Wolfman, published May 13, 1993, describes uses of proteins with bone stimulating activity such as bone fracture healing and possibly the treatment of periodontal disease and other tooth repair processes.
Thus, growth factors, their receptors, and DNA or RNA coding sequences therefore and fragments thereof are useful in a number of therapeutic, clinical, research, diagnostic, and drug design applications.